Variant classification summary

NM_000314.8:c.548del

PTEN · NP_000305.3:p.(Lys183ArgfsTer16) · NM_000314.8

GRCh37: chr10:89711927 TA>T · GRCh38: chr10:87952170 TA>T

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys183ArgfsTer16)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN NM_000314.8:c.548del (NP_000305.3:p.(Lys183ArgfsTer16), p.(K183Rfs*16)) variant has been observed in somatic cancer databases once in COSMIC and has been reported in ClinVar as Pathogenic by a clinical laboratory.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%).

3

This variant is a frameshift predicted to create a premature termination codon, and because c.548 is upstream of the PTEN Expert Panel p.D375 (c.1121) truncation threshold in transcript NM_000314.8, the finding is consistent with full-strength PVS1.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03.

Final determination: Rule20 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	NM_000314.8:c.548del is a PTEN frameshift variant predicted to result in p.(Lys183ArgfsTer16) / p.(K183Rfs*16). Under the PTEN Expert Panel PVS1 decision tree, truncating variants at or 5' to p.D375 (c.1121) in transcript NM_000314.8 meet full-strength PVS1; c.548 is upstream of this threshold and PTEN loss of function is an established disease mechanism.	cspec vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n pvs1_gene_context pvs1_variant_assessment
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) overall and below the subpopulation requirement of <0.00002 (0.002%), supporting PM2 at the Supporting level.	gnomad_v2 gnomad_v4 cspec
PS4	Not assessed	This variant has been reported in ClinVar as Pathogenic and has one somatic observation in COSMIC, but no case-count or case-control data were identified that establish the PTEN-specific phenotype specificity score required for PS4.	clinvar PMID:29296277 cspec
PS3	Not assessed	No variant-specific functional study meeting PTEN Expert Panel PS3 requirements was identified for this frameshift variant. The PTEN saturation mutagenesis functional dataset referenced for PS3 applies to missense variants and does not provide applicable evidence for this deletion.	cspec vcep_m_m_c_2
BS3	Not assessed	No functional study showing normal PTEN function was identified for this frameshift variant. The PTEN saturation mutagenesis dataset referenced for BS3 applies to missense variants and does not provide benign functional evidence for this deletion.	cspec vcep_m_m_c_2
PP3	N/A	This is a coding frameshift variant rather than a missense or noncoding splice-prediction case. SpliceAI shows a low maximum delta score of 0.03, but PTEN Expert Panel PP3 is intended for missense variants with REVEL >0.7 or splicing variants with concordant splice-prediction evidence, so PP3 is not applied.	cspec spliceai
BP4	N/A	This is a coding frameshift variant rather than a missense or noncoding splice-prediction case. SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, but PTEN Expert Panel BP4 is intended for missense variants with REVEL <0.5 or splicing variants with concordant benign splice-prediction evidence, so BP4 is not applied.	cspec spliceai
PM1	Not met	The protein change begins at Lys183, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168). Cancer Hotspots also did not identify this site as a statistically significant hotspot, so PM1 is not met.	cspec hotspots
PM4	N/A	This variant is a frameshift deletion, not an in-frame insertion/deletion or stop-loss variant. PTEN Expert Panel PM4 is therefore not applicable.	cspec
PS1	N/A	This variant is a frameshift deletion and does not represent an alternate nucleotide change producing the same amino acid substitution as a previously established pathogenic variant. PS1 is not applicable.	cspec
PM5	N/A	PM5 is a missense-specific criterion for a different pathogenic missense change at the same residue. This variant is a frameshift deletion, so PM5 is not applicable.	cspec
PP2	N/A	PP2 is a missense-specific criterion. This variant is a frameshift deletion, so PP2 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo observation with maternity and paternity established was identified for this variant. PS2 cannot be applied without documented de novo evidence in an affected individual with no family history.	cspec PMID:29296277
PM6	Not assessed	No assumed de novo observation without parental confirmation was identified for this variant. PM6 cannot be applied without documented de novo evidence in an affected individual.	cspec PMID:29296277
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the PTEN BA1 threshold of >0.00056 (0.056%), so BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the PTEN BS1 thresholds of 0.0000043-0.000043 for Supporting and 0.000043-0.00056 for Strong, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, and no homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified. BS2 is not met.	gnomad_v2 gnomad_v4 cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeatedly in cis/phase unknown with other pathogenic PTEN variants. BP2 cannot be applied.	cspec
BP5	Not assessed	No evidence was identified that this variant occurred in a case with an alternate highly penetrant molecular explanation for the phenotype and no clinical overlap with PTEN-related disease. BP5 cannot be applied.	cspec
BP7	N/A	BP7 applies to synonymous or deep intronic variants. This variant is a coding frameshift deletion, so BP7 is not applicable.	cspec
PP4	N/A	The PTEN Expert Panel specification designates PP4 as not applicable.	cspec
BP6	N/A	The PTEN Expert Panel specification designates BP6 as not applicable.	cspec
BP1	N/A	The PTEN Expert Panel specification designates BP1 as not applicable.	cspec
PM3	N/A	The PTEN Expert Panel specification designates PM3 as not applicable.	cspec
PP5	N/A	The PTEN Expert Panel specification designates PP5 as not applicable.	cspec
BP3	N/A	The PTEN Expert Panel specification designates BP3 as not applicable.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.